Results of a multigene panel testing approach targeting patients with suspected genetic predisposition to pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma occur in the context of a suspected or proven genetic predisposition in 5-10% of cases. While universal germline multigene panel testing is currently recommended by NCCN and ASCO, this approach was previously limited to patients with personal and/or family criteria suggestive of hereditary predisposition. We report the results of this « selective » approach applied in our institution from January 2018 to June 2023. Germline testing of a panel of 13 « clinically actionable » genes (APC, ATM, BRCA1, BRCA2, CDKN2A, MLH1, MSH2, MSH6, PALB2, PMS2, RAD51C, RAD51D, STK11) was performed in 496 patients with pancreatic ductal adenocarcinoma and suspected genetic predisposition based on the validation of prespecified clinical criteria. A germline pathogenic/likely pathogenic variant of one of these genes was identified in 49 patients corresponding to 9.9% of the study population. ATM and BRCA2 were the two most frequently implicated genes (18 and 16 cases, respectively) and the prevalence of pathogenic/likely pathogenic variants of these genes was significantly higher than in gnomAD controls. The overall contribution of core and non-core genes of the Homologous Recombination DNA repair system was 83.7% while the contribution of the Mismatch Repair system was 10.2%. An exploratory approach consisting of unmasking the results of the NGS analysis of 123 « research » genes involved in the carcinogenesis was applied to the 447 patients tested negative for the different genes of our diagnostic panel. This approach failed to identify other susceptibility genes to pancreatic adenocarcinoma.